PB2541: RARE CAP +41 TO +44 [HBB:C.11_-8DELAAAC]/NI MUTATION IN THE 5;UTR OF THE Β GLOBIN GENE IN A GREEK MALE AND GENETIC COUNSELING.
Authors: Stamatia Theodoridou, Evaggelia-Eleni Delaki, Eleni Yfanti, Aikaterini Teli, Genovefa Mantzou, Christina Karipidou, Maria Dimopoulou
Journal: HemaSphere (2023)

Topic: 27. Thalassemias Background: Hemoglobinopathies are of the most extensively studied genetic diseases with different phenotype expression. Rare mutations that are silent are identified with molecular testing. One of the “silent” β mutations within the 5’ and 3’ untranslated region (UTRs) of HBB was once reported in a Chinese female with no available hematological data. Aims: Since then, no available references are found for this rare mutation either in heterozygote state either in patients with thalassemia intermedia. We report the case of a 36- year- old male from Northern Greece who was found to be a carrier of the 5’UTR; +41 to + 44 [HBB: c.-11-8delAAAC]/NI mutation. Methods: The propositus was referred for hemoglobinopathy screening along with his wife. Carrier identification is partially carried out by a network of Thalassemia Prevention Units in Greece following a standard scheme that includes hematological analysis, high performance liquid chromatography (HPLC), capillary electrophoresis (CE) and genetic analysis when required. Results: Proband’s hematological data were Hb level of 15.2 g/dL, red blood cell (RBC) count of 5.00 x 106/ml, mean corpuscular volume (MCV) 92.1 fL, mean corpuscular Hb (MCH) 30.5pg, with ferritin level 24 ng/mL, negative sickle cell test. Peripheral blood smear showed anisocytosis and HPLC analysis of hemoglobin (Biorad- Variant) showed no unknown fractions and Hb A2 3.4% and Hb F 0.5%. Proband’s wife screening revealed Hb level of 11.0 g/dL, red blood cell (RBC) count of 5.58 x 106/ml, mean corpuscular volume (MCV) 64.0 fL, mean corpuscular Hb (MCH) 19.7 pg, with ferritin level 33 ng/mL, Ηb A2 4,9% and Hb F 1,5%. Further genetic analysis was performed after informed consent of the couple. Surprisingly we were in front of a 5’UTR; +41 to + 44 (-AAAC) mutation in heterozygous state in the proband while the female’s genetic analysis showed triplicated α gene and IVSI-110 G>A/NI. Since the first report in China no available references are found for this rare mutation either in heterozygote state either in patients with thalassemia intermedia. Several mutations involving this region which is transcribed but not translated have been described with variable phenotypes, either completely silent or similar to other forms of β thalassemia with less abnormal indices and marginally elevated Hb A2 levels. Summary/Conclusion: The +41 to + 44 (-AAAC) mutation identified in this region is supposed to be “silent” with evidences of no effect on the translational competition or a relative reduction of the m- RNA production. The hematological phenotype of the heterozygous carrier of this mutation was normal with the only evidence of the slight rise in the level of Hb A2. It is well known that the co-inheritance of triplicated alpha-globin gene with β–thalassemia mutations may convert the asymptomatic β thalassemia carrier to a more severe form of thalassemia intermediate but the hematological indices of the female tested were not indicative for a thalassemia intermedia phenotype. Genetic counseling for the combination of IVSI-110 and 5’UTR; +41 to + 44 (-AAAC) mutation with the co-inheritance of the triplication of alpha-globin gene was made to the couple expressing the limited references and the silent expression of the 5’UTR; +41 to + 44 (-AAAC) mutation. However, interaction of silent mutations with other forms of thalassemia may produce a more severe phenotype. Keywords: Thalassemia